6fcd

Publication Abstract from PubMed

Methylation is an underpinning process of life and provides control for biological processes such as DNA synthesis, cell growth, and apoptosis. Methionine adenosyltransferases (MAT) produce the cellular methyl donor, S-Adenosylmethionine (SAMe). Dysregulation of SAMe level is a relevant event in many diseases, including cancers such as hepatocellular carcinoma and colon cancer. In addition, mutation of Arg264 in MATalpha1 causes isolated persistent hypermethioninemia, which is characterized by low activity of the enzyme in liver and high level of plasma methionine. In mammals, MATalpha1/alpha2 and MATbetaV1/V2 are the catalytic and the major form of regulatory subunits, respectively. A gating loop comprising residues 113-131 is located beside the active site of catalytic subunits (MATalpha1/alpha2) and provides controlled access to the active site. Here, we provide evidence of how the gating loop facilitates the catalysis and define some of the key elements that control the catalytic efficiency. Mutation of several residues of MATalpha2 including Gln113, Ser114, and Arg264 lead to partial or total loss of enzymatic activity, demonstrating their critical role in catalysis. The enzymatic activity of the mutated enzymes is restored to varying degrees upon complex formation with MATbetaV1 or MATbetaV2, endorsing its role as an allosteric regulator of MATalpha2 in response to the levels of methionine or SAMe. Finally, the protein-protein interacting surface formed in MATalpha2:MATbeta complexes is explored to demonstrate that several quinolone-based compounds modulate the activity of MATalpha2 and its mutants, providing a rational for chemical design/intervention responsive to the level of SAMe in the cellular environment. ENZYMES: Methionine adenosyltransferase (EC.2.5.1.6). DATABASE: Structural data are available in the RCSB PDB database under the PDB ID 6FBN (Q113A), 6FBP (S114A: P221 21 ), 6FBO (S114A: I222), 6FCB (P115G), 6FCD (R264A), 6FAJ (wtMATalpha2: apo), 6G6R (wtMATalpha2: holo).

Control and regulation of S-Adenosylmethionine biosynthesis by the regulatory beta subunit and quinolone-based compounds.,Panmanee J, Bradley-Clarke J, Mato JM, O'Neill PM, Antonyuk SV, Hasnain SS FEBS J. 2019 Feb 18. doi: 10.1111/febs.14790. PMID:30776190^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.